It's kind of bugging me to see reviews state that Macfarlane "bombed" with the theater audience. I rewatched the opening and they were laughing their asses off, and were with him through much of the night.
And even the shocked reaction to his John Wilkes Booth joke was exactly the kind of response you're looking for with a joke like that.
One joke bombed, and that was the Chris Brown one. Only Robert Downey Jr laughed/applauded that one. Otherwise, I think he killed his parts, a lot of the rest fell flat.